Body fluid replacement solution

ABSTRACT

A sterile, pyrogen-free fluid replacement solution for intravenous infusion is disclosed that consists essentially of a physiologically acceptable sodium salt, a physiologically acceptable potassium salt, an osmolality control agent, and, optionally, a component selected from the group consisting of a physiologically acceptable calcium salt and a physiologically acceptable magnesium salt.

This application is a 371 PCT/GB95/03032 filed Dec. 22, 1995.

The present invention relates to body fluid replacement solutionssuitable for intravenous infusion.

The normal metabolism of the human body results in more or lesscontinuous losses of Na (sodium), K (potassium) and water and in orderto maintain normal functioning of the body it is essential that thelevels of these in the body should be maintained within more or lessclosely defined limits. Where a patient is unconscious or under a "niloral intake" regime for one reason or another e.g. pre- orpost-operative, then it is necessary for these levels to be maintainedby intravenous infusion of suitable solutions. Also in cases of shock itis normal practice to increase the volume of fluid in the circulation inorder to maintain blood pressure within safe limits.

Conventional medical practice is based on the administration of standard"quantities of solutions of dextrose (5% w/v aqueous) and physiologicalsaline (0.9% w/v aqueous NaCl), with the occasional addition ofpotassium salt to one or other of the above solutions. Typicallypatients are provided daily with 2 liters (4×500 ml units) of dextroseand 1 liter (2×500 ml units) of saline with from 0 to 3 ampoules ofaqueous potassium chloride (15% w/v KCl) incorporated into one of thedextrose or saline units. These dosages are however usually appliedwithout regard to the patients' bodyweight which has a substantialeffect on the K/Na requirements--e.g. the requirements for a 100 kgpatient will generally be 100% higher than those for a 50 kg patient. Asa result many patients receive incorrect amounts of K and/or Na. Thiscan have quite serious consequences which can aggravate a patient'scondition rather than stabilise or help to improve it. Thus excess Nacan result in edema whilst too little Na can give rise to muscularcontractions and cramps. High or low levels of K can induce arrhythmiasof the heart.

In the past a wide variety of body fluid replacement solutions have beenproposed for various purposes. Many of these include bicarbonate (HCO₃),stabilized by packing under carbon dioxide (Co₂) given in bicarbonateprecursors such as acetate or lactate. These can affect the CO₂ :HCO₃balance in the body and give rise to adverse effects on the patient ifthey are not carefully controlled. Such adverse effects can moreover beparticularly serious in the case of patients who have an underlyingproblem such as acidosis resulting from kidney failure or CO₂ retentionin the lungs, or alkalosis resulting from respiratory problems withexcessive loss of CO₂ from the lungs. If the solution used has a pHand/or HCO₃ /CO₂ bias which aggravates that of the underlying condition,then the patient's condition may be seriously exacerbated.

Insofar as bodyfluid replacement solutions are often used in emergencysituations and/or in a very routine manner i.e. without detailedconsideration of the patient's specific requirements there isaccordingly a need for a solution which can be used with a high degreeof safety as easily as possible. It is an object of the presentinvention to avoid or minimize one or more of the abovementioneddisadvantages of the prior art.

The present invention provides a sterile pyrogen-free body fluidelectrolyte replacement solution for intravenous infusion and consistingessentially of an aqueous solution containing from 30 to 100 mMol Na(per 1000 mls) as a physiologically acceptable salt; from 15 to 50 mMolK (per 1000 mls) as a physiologically acceptable salt; an effectiveamount of a physiologically acceptable osmolality control agent forproviding an osmolality of from 260 to 320 mOsm per kg of solution, saidsolution being substantially free of material having a molecular weightgreater than 5000, and substantially free of any material capable ofsignificantly affecting acid-base balance in vivo.

Thus with a solution of the present invention it is possible to provideeffective body fluid replacement and critical electrolyte balance in asafe manner with a minimal risk of undesired complications or adverseeffects. Moreover by simply adjusting the volume given approximately tothe bodyweight of the patient, optimum body fluid replacement can beachieved in a particularly simple and convenient manner.

Various physiologically acceptable salts may be used in the solutions ofthe invention though chloride, sulphate and phosphate are particularlyconvenient, especially chloride.

Whilst it is a particular feature of the present invention that thesolutions are substantially free of any other components (therebyminimizing any possible side effects), it will be understood, that otherphysiologically acceptable substances could be included, if desired,e.g. for nutritional purposes, in small amounts which do notsignificantly or adversely perturb the metabolism. Thus for examplethere could be included preferably not more than 5 mMol of calcium andnot more than 10 mMol of Magnesium (per litre of solution). Preferablythe solutions are substantially free of bicarbonate, and most preferablycontain not more than 5 mMol of bicarbonate or a precursor (per liter ofsolution).

Preferably there is used a non-ionic osmolality control agent, whichdesirably is substantially water soluble. Suitable agents that may bementioned include dextrose, fructose, glucose and other sugars which areeasily metabolised. Desirably also the agent should be substantiallynon-vasoactive i.e. does not change the vasculature and the diameter ofthe veins. Preferably the agent is used in an amount providing anosmolality of from 280 to 300 mOsm per kg of solution.

Whilst the pH of the solutions of the invention will generally be in therange from 5 to 8.5, this is not a particularly critical considerationinsofar as the low concentrations of the solution components are more orless readily buffered within the body.

The solution of the present invention is preferably administered at adaily rate of from 20 to 40 mls, preferably 25 to 35 mls, for exampleabout 30 mls, per kg bodyweight of the patient. Thus for a typicalbodyweight of 50 kg the preferred daily administration rate would beabout 1500 mls, whilst for an 80 kg patient it would be about 2400 mls.

Advantageously the solution of the invention is presented inpredetermined volume units of from 1500 to 3500 mls, most preferablyabout 1500 to 2400 mls, so that a suitable amount for a given patientbodyweight may readily be provided by selecting a suitably sized unite.g. 1500 mls for around 50 Kg bodyweight (say 45 to 55 Kg bodyweight),1800 mls for 60 Kg, 2100 mls for 70 Kg, 2400 mls for 80 Kg etc.

In further aspects the present invention provides a method of replacingbody fluid and a method of maintaining electrolyte balance, eachcomprising the steps of determining at least an approximate indicationof patient bodyweight, and administering to the patient a solution ofthe invention at a daily rate of from 25 to 35 mls per kg bodyweight perday.

Ideally the solution of the invention is administered more or lesscontinuously i.e. one daily unit is administered over 24 hours. Moreconveniently though the solution may be administered over a period of atleast 14 hours, preferably from 14 to 28 hours.

Further preferred features of the invention will appear from thefollowing detailed examples given by way of illustration only alongsidean example of the prior art.

EXAMPLE 1 Prior Art Design of Fluid Therapy Regimen

Most patients are given three liters of IV fluid daily.

    ______________________________________                                        1 × 500 ml normal saline infusion                                                               followed by                                           1 × 500 mg glucose 5% infusion                                                                  followed by                                           1 × 500 ml glucose 5% infusion                                                                  followed by                                           1 × 500 ml saline infusion                                                                      followed by                                           1 × 500 ml glucose 5% infusion                                                                  followed by                                           1 × 500 ml glucose 5% infusion                                          ______________________________________                                    

One or two ampoules of 15% potassium chloride infusion may or may not beadded to one or more of these infusions to provide the potassiumrequirement.

IV fluid therapy in this situation requires six prescription lines to bewritten, six changes of container for the patient, six entries on thefluid balance charts and up to perhaps two aseptic manipulations inorder to add the potassium chloride injection into the regimen. Littleattention is paid to providing amounts of water, sodium or potassiumwhich are appropriate for the individual patient. Fluid overload andoedema are not surprisingly common problems in the hospital wardsituation.

EXAMPLE 2 Body Fluid Replacement Solution

A body fluid replacement solution was prepared using BP or USP or someother pharmaceutically accepted grade ingredients as follows understerile conditions and sealed into a conventional body fluid containerin the form of a sterile plastics bag provided with adapter means forcoupling to a giving set or the like. The solution was prepared usingsodium chloride 3.861g, potassium chloride 2.475g and glucose 18.5g in 1liter of water for injections. A range of predetermined volumes of thisstandard solution was made available to broadly satisfy the baselinewater, sodium, and potassium requirements of various weights of patientas follows:

    ______________________________________                                        Patient weight range                                                                         Appropriate volume                                             ______________________________________                                        45-55 kg       1500 ml                                                        55-65 kg       1800 ml                                                        65-75 kg       2100 ml                                                        75-85 kg       2400 ml                                                        ______________________________________                                    

The above described solution had a sodium content of 66.7 mMol,potassium content of 33.3 mMol, chloride content of 100 mMol and glucosecontent of 102.5 mMol per liter, an osmolality of 290 mOsm/kg, andcontained less than 0.01% of other components.

EXAMPLE 3 Use of Body Fluid Replacement Solution

A suitably sized body fluid replacement solution unit from Example 2 wasselected according to the patient's bodyweight (e.g. a 1500 ml unit fora 48 kg patient) to provide the complete daily requirement for thatpatient in one single container. The solution may be administered inconventional manner but with the significant advantages that only onebag will be required each day to provide the patients daily baselinerequirements so that there is only one prescription line required, oneentry on the patient's fluid balance chart and one change over of givingset required each day. The new solution thus simplies IV fluid therapywhile providing a more physiologically suitable solution for thepatient.

EXAMPLE 4 Clinical Trial Comparison of Use of Body Fluid ReplacementSolutions of the Invention and Conventional Intravenous Infusion Therapy

A clinical trial on the safety of the new invention solutions wascarried out. After obtaining patient consent, a group of approximately100 surgical patients undergoing laparoscopic cholecystectomy wererandomised into: a control group which would receive conventional IVinfusion therapy, or a trial group receiving body fluid replacementsolutions according to the present invention. 50 patients were allocatedinto each group.

The conventional therapy was generally 3 liters of fluid per daycomprised of 2×500 ml infusions of sodium chloride 0.9% w/v and 4×500 mlof dextrose 5% w/v infusion.

The solution units according to the present invention were selecteddependent on patient weight as follows:

    ______________________________________                                        Invention                                                                             Patient    sodium   potassium                                         Solution                                                                              weight(Kg) (mMol)   (mMol)  volume (ml)                               ______________________________________                                        "50 kg" 45-54      100      50      1500                                      "60 kg" 55-65      120      60      1800                                      "70 kg" 65+        140      70      2100                                      ______________________________________                                    

Each solution was adjusted to an osmolality of 290 with glucose(dextrose). One appropriate solution unit was administered each day overa period of 24 hours at a constant rate. Patients were closely observedfor signs of hyper or hypokalaemia, hyper or hyponatremia and any fluidimbalance problems.

Biochemical Monitoring

Daily blood samples were taken from all the patients for the duration ofthe fluid replacement therapy. These were analysed for plasma sodium,potassium, glucose, creatinine and urea values and the change inconcentration in mMol/liter, relative to the patient's initial startingvalue, was noted.

    ______________________________________                                        Biochemical Monitoring Results                                                               day 1 day 2   day 3   day 4                                    ______________________________________                                        1. Sodium (Normal range: 135 to 145 mMol/liter)                               Invention solution                                                            Change in sodium 0.22    0.92    0.72  0.33                                   Standard deviation                                                                             1.69    2.32    2.06  1.77                                   Conventional IV therapy group                                                 Change in sodium 0.26    0.74    0.51  0.25                                   Standard deviation                                                                             1.06    2.64    1.5   1.01                                   2. Potassium (Normal range: 3.5 to 5.5 mMol/liter)                            Invention solution group                                                      Change in potassium                                                                            0.045   0.05    0.06  0.02                                   Standard deviation                                                                             0.293   0.22    0.25  0.27                                   Conventional IV therapy group                                                 Change in potassium                                                                            0.005   0.05    0.05  0.005                                  Standard deviation                                                                             0.256   0.25    0.25  0.13                                   3. Urea (Normal range: 3 to 5 mMol/liter)                                     Invention Solution                                                            Change in urea   0.23    0.15    -0.18 -0.3                                   Standard deviation                                                                             1.0     1.43    1.57  1.4                                    Conventional IV Therapy Group                                                 Change in urea   -0.64   -0.90   -1.06 -1.55                                  Standard deviation                                                                             0.53    0.98    1.24  0.96                                   ______________________________________                                    

There were no significant differences between the changes in the sodiumand potassium levels between the invention solution group and theconventional therapy group. However, there was a significant differencein the two groups in the urea level. A decrease in urea level is one ofthe biochemical signs of overhydration. The conventional therapy groupindicated a significant number of patients to be overhydrated. Inaddition the longer the therapy was given the greater the extent towhich this problem developed.

Comparison of the time involved in set up and recording of conventionalIV therapy and use of inventions solutions.

The amount of time taken to set up the invention solution treatment andthe conventional therapy was recorded and the following resultsobtained.

    ______________________________________                                        Setting up time in a 24 hour period                                           Time to set up                                                                invention solution bag   3 mins                                               conventional therapy     18 mins                                              Time to prepare prescription                                                  invention solution       2 mins                                               conventional therapy     8 mins                                               Time to record fluid administration                                           invention solution       4 mins                                               conventional therapy     24 mins                                              Total time for implementing body fluid replacement                            Invention solution system = 9 mins                                            Conventional IV therapy = 50 mins                                             ______________________________________                                    

The invention solution system is therefore far less time consuming toset up and record than conventional therapy.

Conclusions

The trial demonstrated no significant changes in plasma urea andelectrolytes in those patients receiving the invention solution andconfirms that it effectively maintains the required levels. The drop inurea with the conventional therapy group confirms the suspicion that thelatter frequently results in fluid overload in a significant number ofpatients. The invention solution system takes significantly less time toset up and make the relevant recordings than does the conventionaltherapy.

I claim:
 1. A sterile pyrogen-free body fluid replacement solution forintravenous infusion consisting essentially of from 30 to 100 mMol Na(per 1000 mls) as a physiologically acceptable salt; from 15 to 50 mMolK (per 1000 mls) as a physiologically acceptable salt; an effectiveamount of a physiologically acceptable osmolality control agent forproviding an osmolality of from 260 to 320 mOsm per kg of solution, saidsolution being substantially free of material having a molecular weightgreater than 5000, and substantially free of in vivo pH biasing agentand in vivo bicarbonate-carbon dioxide balance biasing agent; and,optionally, a component selected from the group consisting of not morethan 5 mMol of calcium and not more than 10 mMol of magnesium (per 1000mls) as a physiologically acceptable salt.
 2. A solution as claimed inclaim 1 wherein each said physiologically acceptable salt is selectedfrom chloride, sulphate and phosphate.
 3. A solution as claimed in claim1 wherein said osmolality control agent comprises a non-ionic osmolalitycontrol agent.
 4. A solution as claimed in claim 3 wherein said agent issubstantially water soluble.
 5. A solution as claimed in claim 4 whereinsaid agent comprises an easily metabolized sugar.
 6. A solution asclaimed in claim 5 wherein said agent is substantially non-vasoactive.7. A solution as claimed in claim 3 wherein the agent is used in anamount providing an osmolality of from 280 to 300 mOsm per kg ofsolution.
 8. A solution as claimed in claim 3 which solution containsnot more than 5 mMol of bicarbonate or a precursor thereof (per 1000 mlsof solution).
 9. A solution as claimed in claim 1 which is substantiallyfree of each of bicarbonate, lactate and acetate.